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Extended nuclear glycosylation is a common post-translational modification

Lundstrom, J.; Fong, M.; Thorsell, A.; Mirgorodskaya, E.; Fuchs, J.; Bashir, U.; Hintzen, J. C. J.; Jin, C.; Mohideen, F. I.; Lobo, V.; Shcherbinina, E.; Tietze, A. A.; Mahal, L. K.; Sarshad, A.; Bojar, D.

2025-12-02 molecular biology
10.64898/2025.12.02.691741 bioRxiv
Show abstract

In eukaryotes, glycans modify proteins in the secretory pathway and the extracellular space. Aside from nucleocytoplasmic O-GlcNAc, glycosylation is not thought to be a relevant post-translational modification in other cellular compartments. Here, we challenge this long-standing paradigm with data-driven and experimental evidence, showing that extended O-glycans are commonly found on proteins inside mammalian nuclei. Through comprehensive genetic and biochemical analyses, we conclusively demonstrate that these O-glycans stem from the secretory pathway, yet are found on nuclear proteins across various mammalian cell lines and primary cells. Using knock-out cell lines, we also show mechanistically that nuclear glycans are shuttled to the nucleus via active vesicular transport. We identify several of these intra-nuclear glycoproteins as RNA-binding proteins, including KHSRP/FUBP2 and RBM12. Overall, our findings suggest a much broader role for glycosylation as a regulator of cellular functions and opens up investigation into the role of glycans in many more biological processes.

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